EP4494756A1 - Apparatus and laboratory device for incubating multiple patient samples using multiple incubation vessels - Google Patents

Abstract

A device is proposed for incubating a plurality of patient samples using a plurality of incubation vessels, comprising a first unit with respective receptacles for respective incubation vessels, and a second unit with respective receptacles for respective incubation vessels, wherein both of the respective units are each mounted so as to be movable in their respective location position along a common linear guide axis, further comprising respective sensors for providing respective sensor signals, which each indicate one of the respective location positions, further comprising respective magnetic drive units for a respective change in a respective location position, and further comprising a control unit which is designed to control the respective magnetic drive units on the basis of the respective sensor signals in order to bring about the respective changes in the respective location positions.

Description

The invention relates to a device and a laboratory machine for incubating several patient samples using several incubation vessels.

A large number of technical processes in the fields of biotechnology, pharmacy, diagnostics and medicine have the task of incubating several or respective patient samples in respective incubation vessels. Incubation is understood here as bringing a patient sample into contact with one or more liquids of a so-called assay or diagnostic assay. For this to happen, the patient sample must not only be brought into contact with one or more such liquids of an assay for a short time, but the corresponding incubation vessel must hold the patient sample and other liquids for a certain period of time. In order to optimize the mixing of the patient samples and such liquids, the incubation vessel is usually moved or shaken rhythmically. Furthermore, the incubation vessel can also preferably be exposed to a predetermined temperature, which then prevails inside the incubation vessel.

For such purposes, it is desirable to increase the degree of automation of such incubation processes for logistical and also economic reasons.

Devices are known in which a single incubation vessel is placed in a holder and in which the incubation vessel is then rhythmically moved or shaken by an automated movement of the holder.

The object of the present invention is to further increase the degree of automation so that an incubation of several patient samples in corresponding or respective incubation vessels can take place at least partially simultaneously.

The object of the invention is achieved by a device according to claim 1 and a laboratory machine according to claim 11.

The device according to the invention for incubating several patient samples has a first unit with respective, i.e. several, receptacles for respective incubation vessels as well as a second unit with respective, i.e. several, receptacles for respective incubation vessels.

Both units are mounted so that they can move in their respective positions along a common linear guide axis.

The device further comprises respective sensors for providing respective sensor signals, wherein the respective sensor signals each indicate one of the respective location positions of a respective unit.

Furthermore, the device has respective magnetic drives or magnetic drive units, which are each designed to effect or bring about a respective change in a respective location position of a respective unit.

Finally, the device further comprises a control unit which is designed to control the respective magnetic drive units on the basis of the respective sensor signals in order to bring about or effect the respective changes in the respective location positions.

The device according to the invention provides that two units each have several incubation vessel receptacles, so that a plurality of incubation vessels can be subjected to a rhythmic movement or a shaking process at the same time. Because both units are movably mounted along the common linear guide axis, these two units can only move translationally along this axis, in particular can only be set into vibration along this axis. In particular, the two units are mounted and guided in such a way that they only have one common translational degree of freedom along the common linear guide axis. This makes it possible in principle for the mass movements of the two units with the incubation vessels located therein to not take place in a disorderly or chaotic manner, but only along the common linear guide axis, so that in principle these two mass movements can compensate for each other, in particular if the device is installed in an entire laboratory machine.

Because the control unit has knowledge of the respective positions of the respective units based on the respective sensor signals of the respective sensors, the control unit can advantageously use the respective magnetic drive units to bring about a respective change in a respective position on the respective unit. If only a single unit were used for incubation, a rhythmic movement of this individual unit would affect the entire laboratory machine and thus possibly also cause other units in the laboratory machine to vibrate. By providing two separate units which are mounted so as to be movable in the direction of the common linear guide axis, such a mass movement of an individual unit can be compensated for by a mass movement of the second unit. In particular, the control unit controls the magnetic drive units in such a way that a mass movement of the first unit is compensated for by a mass movement of the second unit. This minimizes the overall mass movement of the total mass of the units and thus also minimizes any mechanical impact on the entire laboratory machine.

Advantageous embodiments of the invention are the subject of the dependent claims and are explained in more detail in the description with partial reference to the figures.

Preferably, the two units are each mounted and guided along the common linear guide axis in such a way that they only have one common translational degree of freedom. This ensures that the mass movements of the units only take place along the one linear guide axis or the one translational degree of freedom and thus the control unit only has to be designed to control the mass movements of the respective units only along this translational degree of freedom or along this common linear guide axis in such a way that the mass movements compensate each other to at least a certain degree.

Preferably, a respective unit is mechanically coupled to a common base plate via a respective spring unit. In this case, a respective unit together with a respective spring unit preferably forms a respective spring-mass oscillation system. This design is advantageous because the control unit can thus cause the respective units to oscillate at a specific frequency via the respective magnetic drive units. In this case, the control unit can utilize the frequency response of a respective spring-mass oscillation system and preferably only has to generate drive energy via the magnetic drive units in such a way that possible energy losses due to mechanical friction and/or deviations of the oscillation frequencies of the spring-mass oscillation systems from a target frequency compensate. The control unit is therefore preferably designed to cause the respective units, in particular the respective magnetic drive units, to oscillate at the same frequency.

The control unit is further preferably designed to control the magnetic drive units in such a way that the units are each kept oscillating with a substantially equal oscillation amplitude in the direction of the linear guide axis or the translational degree of freedom. The oscillation amplitudes can also be referred to as maximum oscillation amplitudes.

In particular, the control unit is preferably designed to control the magnetic drive units using a control principle based on the sensor signals such that the resulting respective oscillation frequencies of the respective units are essentially the same and that the respective oscillation frequencies have a phase offset of essentially 180 degrees from one another. Particularly preferably, the resulting respective oscillation frequencies of the respective units are the same and have a phase offset of 180 degrees from one another. This configuration is particularly advantageous because compensation of a mass movement of the first unit compared to a mass movement of the second unit is then particularly optimized or enabled, so that in particular the overall effect of vibration forces of the two common units on a laboratory machine is particularly minimized.

In particular, the control unit is designed to determine a respective current amplitude or vibration amplitude and a respective vibration frequency for a respective unit on the basis of a respective sensor signal, and also in particular to regulate both units to a common vibration amplitude and a common, identical target vibration frequency. This achieves particularly good optimization of the vibration compensation of the two units. The common vibration amplitude can also be referred to as the common maximum vibration amplitude or as the maximum target vibration amplitude.

In particular, both units preferably have the same mass in the unloaded state. In particular, the two spring units are designed such that they have the same, common spring constant.

Preferably, both units with the respective associated spring unit have a respective spring-mass oscillation system with the same resonance frequency in unloaded state, with a target oscillation frequency of the control unit's regulation lying below this resonance frequency. This design is advantageous because by loading one or both units with incubation vessels, and in particular liquids contained therein, a respective total mass of a respective unit is increased and a resonance frequency is thus reduced from the unloaded state of the system to a somewhat lower resonance frequency. Because the target oscillation frequency of the control unit's regulation lying below the resonance frequency of one of the spring-mass oscillation systems in the unloaded state, it is thus achieved that in the loaded state of the units the target oscillation frequency is close to a resonance frequency of the spring-mass oscillation systems in the loaded state of the units. In particular, the respective units with their respective spring units each form identical spring-mass oscillation systems.

Preferably, the control unit is further designed to carry out a PI control based on a common, identical target oscillation frequency. Furthermore, the control unit is preferably designed to carry out a PI control based on a common, identical target oscillation frequency and a common, identical maximum oscillation amplitude for both units, wherein in particular the respective oscillation frequencies of the respective units have a phase offset of 180 degrees from one another. This design is advantageous because PI controls are particularly stable.

Preferably, each unit has a respective heating unit. This design is advantageous because it enables the desired temperatures to be achieved within the incubation vessels.

A laboratory machine is also proposed, comprising an incubation device according to the invention. The laboratory machine also has a magazine with a plurality of incubation vessels. The laboratory machine also has a container with patient sample liquid, a container with buffer liquid, a container with bead liquid, again comprising beads coated with antigens or antibodies, and a container with a label liquid comprising antibodies or antigens marked with a chemiluminescence label. The laboratory machine is thus in particular a laboratory machine for processing a patient sample using a chemiluminescence assay for detecting a target antigen or a target antibody in the patient sample.

Furthermore, the laboratory machine has a pipetting unit which is designed to dispense at least a portion of the patient sample liquid, at least a portion of the buffer liquid, at least a portion of the bead liquid and at least a portion of the label liquid comprising the antibodies or antigens marked with a chemiluminescence label into the incubation vessels and to aspirate them from the incubation vessels.

The laboratory machine further comprises a gripping unit which is designed to transport incubation vessels from the magazine to the pipetting unit and to transport them from the pipetting unit into respective receptacles, to remove them from the respective receptacles and to transport them back to the pipetting unit. The laboratory machine according to the invention is advantageous because, for the purpose of processing a chemiluminescence assay using antibodies or antigens marked with a chemiluminescence label as part of the assay, patient samples can be incubated or processed in respective incubation vessels in the two units according to the chemiluminescence assay.

Preferably, a laboratory machine is also proposed which has one of the embodiments of the incubation device disclosed herein.

The laboratory machine preferably also has a container with an enzyme for implementing a chemiluminescence reaction and also a reading unit for detecting an optical signal of a chemiluminescence reaction. This design is advantageous because an optical signal of a chemiluminescence reaction can then be generated and detected automatically.

Preferably, the magnetic drives of the device are arranged in such a way that beads contained in the bead liquid are not significantly influenced magnetically by a magnetic field of the magnetic drives. This is advantageous because beads are usually magnetizable particles in the form of metallic beads, which should not be moved by the magnetic drives in a preferred direction or a preferred location during mixing during incubation.

Figur 1A

eine Aufsicht auf eine beispielhafte erfindungsgemäße Vorrichtung

Figur 1B

eine beispielhafte Detailansicht einer Einheit der Vorrichtung gemäß einer bevorzugten Ausführungsform

Figur 2

eine schematische Darstellung der Vorrichtung gemäß einer bevorzugten Ausführungsform

Figur 3

weitere Details einer bevorzugten Ausführungsform der Vorrichtung

Figur 4

eine Prinzipdarstellung einer bevorzugten Ausführungsform eines erfindungsgemäßen Laborautomaten

Figur 5A

ein Zusammenspiel eines Sensors mit einem Magneten

Figur 5B

ein Kennlinienfeld mit Signalen

Figur 6A sowie 6B

Details einer Greifeinheit im Zusammenspiel mit einem Inkubationsgefäß gemäß einer bevorzugten Ausführungsform

Figur 7A sowie 7B

Details von Aufnahmen für Inkubationsgefäße sowie ein Inkubationsgefäß gemäß einer bevorzugten Ausführungsform

Figuren 8A bis 8d

Signale und Frequenzverläufe

Figur 9A

Details einer bevorzugten Ausführungsform einer Teil-Steuereinheit

Figur 9B

weitere Details einer bevorzugten Ausführungsform einer Steuereinheit

Figur 10

Details einer beispielhaften Regelung einer weiteren Teil-Steuereinheit

In the following, the invention is explained in more detail using specific embodiments without limiting the general inventive concept and with reference to the figures. In the figures:

Figure 1A

a plan view of an exemplary device according to the invention

Figure 1B

an exemplary detailed view of a unit of the device according to a preferred embodiment

Figure 2

a schematic representation of the device according to a preferred embodiment

Figure 3

further details of a preferred embodiment of the device

Figure 4

a schematic diagram of a preferred embodiment of a laboratory machine according to the invention

Figure 5A

an interaction of a sensor with a magnet

Figure 5B

a characteristic field with signals

Figures 6A and 6B

Details of a gripping unit in interaction with an incubation vessel according to a preferred embodiment

Figures 7A and 7B

Details of receptacles for incubation vessels and an incubation vessel according to a preferred embodiment

Figures 8A to 8d

signals and frequency responses

Figure 9A

Details of a preferred embodiment of a partial control unit

Figure 9B

further details of a preferred embodiment of a control unit

Figure 10

Details of an exemplary control of another sub-control unit

The Figure 1A shows a device V with two units E1, E2, which have respective receptacles A for respective incubation vessels. The units E1, E2 are guided by linear guides LF along a common linear guide axis LFA, see Figure 1B , movably mounted. Also shown is a control unit SE. The units E1, E2 are mounted on a common base plate GP by means of the linear guide elements LF.

The Figure 1B shows a detailed view of the unit E1 as well as the linear guide elements LF and the base plate GP outlined in dash-dot lines.

The receptacles A are intended to accommodate the respective incubation vessels. A detailed view is shown in the Figure 7A in an orthogonal sectional view, in which a cross-section through the receptacles A is visible as well as an incubation vessel IG introduced into a receptacle A. A corresponding perspective view of such a sectional view is shown in the Figure 7B can be seen, whereby the incubation vessel IG was also placed in a receptacle A.

The Figure 2 shows a preferred embodiment of the device V.

The units E1, E2 are mounted on a base plate GP along a common linear guide axis LFA by means of linear guide units LF1, LF2. The units E1, E2 have respective receptacles A for respective incubation vessels IG. Preferably, the units E1, E2 have respective heating units H1, H2.

The respective units E1, E2 are mechanically decoupled from the common base plate GP by means of respective spring units FE1, FE2. A spring unit FE1 preferably has two spring elements F11, F12. A spring unit FE2 preferably has two spring elements F21, F22.

By means of respective sensors S1, S2, respective sensor signals SIG1, SIG2 can be provided, each of which indicates one of the respective location positions of the respective units E1, E2. For this purpose, the respective sensors S1, S2 preferably detect respective magnetic fields which were generated by respective magnets M1, M2.

A principle for this is in the Figure 5A shown, wherein a sensor S1, S2 is designed in particular as a Hall sensor, so that a translational movement along the linear guide axis LFA of a magnet M1, M2 can be detected. A magnet M1, M2 is in particular a diametrical magnet. The magnets M1, M2 are preferably aligned or positioned centrally in the rest position relative to the respective sensors S1, S2.

The Figure 5B shows a characteristic field KLF, where in an upper right quadrant I a position OP is specified in millimeters, which follows a corresponding sine curve SN1 during a mechanical oscillation. In an upper left quadrant II the resulting magnetic field of the sensor magnet M1, M2 is shown. By using a linear range LB of the corresponding characteristic curve KL2 of the magnetic field, a linear conversion of the position OP can be used, so that in the lower left quadrant III a corresponding Hall voltage is then obtained, which can be converted into a corresponding electrical signal or a corresponding voltage U as a sine curve SN2 according to the lower right quadrant IV.

Such a voltage signal U can then be used as a corresponding signal SIG1, SIG2 according to the Figure 2 provided to the control unit SE.

The control unit SE can control respective magnetic drive units MA1, MA2 by means of respective control signals AS1, AS2. A respective control signal AS1, AS2 is preferably a pulse width modulated signal PWMS, as in Figure 8C The time in seconds is shown on the x-axis, with the time t1 preferably corresponding to a value of t1=(1/16.67) seconds, since the Oscillation frequency is preferably 16.67 Hz. The voltage U of the pulse width modulated signal PWMS is plotted on the y-axis. Such a PWMS signal is present at an output or an interface of the control unit, which preferably has a microcontroller. The maximum signal level of such a pulse width modulated signal PWMS is preferably 3.3 volts.

If such a pulse width modulated signal PWMS is given as a control signal AS1, AS2 to an inverter WR1, WR2, which is connected to a respective coil SP1, SP2, then a corresponding sinusoidal current signal SISIG is produced by the coil, as in Figure 8C The current intensity I of the current signal SISIG is also plotted in amperes on the y-axis. A corresponding magnetic field signal in the vicinity of the coil then results from such a current signal SISIG. The pulse width modulated signal PWMS and the current signal SISIG can in particular have a phase offset from one another.

Such a corresponding magnetic field can then be used so that a respective magnetic drive unit MA1, MA2 moves a respective magnetizable connection plate or return plate AP1, AP2 along the linear guide axis LFA. Preferably, such magnetization of a connection plate AP1, AP2 by the magnetic drive units MA1, MA2 leads to changes in the respective positions of the respective units E1, E2. A respective unit E1, E2 therefore has a respective connection plate or return plate AP1, AP2, which can be attracted or repelled by a respective magnetic drive unit MA1, MA2.

By means of a respective spring assembly FE1, FE2, a respective unit E1, E2 forms a spring-mass oscillation system, whereby in particular the respective units E1, E2 are mechanically coupled to a common base plate GP via the respective spring assemblies FE1, FE2. When the units E1, E2 are coupled to the common base plate GP via the spring units FE1, FE2, it is therefore in principle possible for both units E1, E2 to move along the linear guide axis LFA or the translational direction TR in such a way that their respective movements run in opposite directions or are offset by 180 degrees and thus these respective movements compensate for one another. The spring units FE1, FE2 are preferably formed by compression springs F11, F12, F21, F22.

A unit E1, E2 preferably has a mass of 2.5 kg. A spring unit FE1, FE2 preferably has a spring constant of approximately 11 N/mm ² to 12 N/mm ² . A unit E1, E2 preferably carries out a sinusoidal oscillation, which in the Figure 8A is shown. The y-axis shows the oscillation amplitude or position in millimeters and the x-axis shows the time in seconds.

The design as a spring-mass oscillation system with a magnetic drive is more energy efficient than a purely magnetically driven system. For a purely magnetically driven system without springs, controlling the magnetic drives through the control unit would require more drive energy to change the position in order to generate an oscillation. A spring-mass oscillation system can initially be set into oscillation and then only energy needs to be applied to maintain the oscillation.

Since a chemilumescence assay in particular uses bead liquid containing magnetizable beads in the incubation vessels, the beads must not be magnetically attracted, so that the induction of the oscillating movement by a spring-mass oscillation system is particularly favored, so that particularly high magnetic fields or forces do not have to be built up, which could have a negative effect on the positioning of the magnetizable beads in the incubation vessels. Figure 3 shows once again a special sectional view of a preferred embodiment of a device V with a unit E1 and corresponding receptacles A, wherein the unit E1 is mechanically coupled to the base plate GP via the spring unit FE1. The control unit SE controls the oscillating magnet having a coil SP1 and an inverter WR1. The return plate AP1 can thus be influenced to influence an oscillation frequency of the unit E1 using the resulting magnetic field of the coil SP1. In particular, mechanical friction losses are minimized in order to maintain the oscillation frequency or target oscillation frequency.

The units E1, E2 can be heated to 37 degrees Celsius using the heating units H1, H2. Preferably, a unit E1, E2 has 100 receptacles A for reaction vessels or incubation vessels IG. To ensure thorough mixing of the assay reagents, the incubation plates are set in vibration. The target frequency of such vibration is preferably 16 Hz to 17 Hz and the vibration amplitude is preferably 1 mm. The magnetic beads contained in the reagents or the bead liquid have a higher density than a liquid in which the beads are located within the incubation vessels. Therefore, the frequency and amplitude of the oscillation prevent sedimentation of the beads, but preferably at the same time allow an incubation vessel to be picked up by a gripping unit during operation.

The proposed laboratory machine LA is therefore preferably a so-called random access device, in which a gripping unit G can insert incubation vessels IG into corresponding receptacles A and also remove them again during ongoing operation or during continuous oscillation of the units E1, E2 of the device V.

This is achieved in particular by the gripping unit applying a force to an edge R of an incubation vessel IG, see Figures 6A and 6B , from above by a sub-unit T2 and from below by a sub-unit T1, so that only frictional forces are generated in the translational direction, by means of which an incubation vessel IG is held in a gripping unit G. In directions other than the translational direction, in particular a positive gripping takes place. Because a frictional gripping takes place in the translational direction - and in particular preferably no positive gripping - the incubation vessel IG can continue to carry out minimal movements in a receptacle A and in the translational direction during the gripping process, which are generated in particular by a movement of the units E1, E2, until in particular an incubation vessel IG has been removed so far upwards from the receptacle A until in particular sufficient distance has been created between the chronically converging lower area UB of the incubation vessel IG and the side walls SAE of the receptacle Ae, see also Figures 7A and 7B .

The Figure 8B shows a frequency response in the form of a characteristic curve LK for a case in which a unit E1, E2 is unloaded. A frequency f in Hertz is plotted on the x-axis and a standardized frequency response N(f) on the y-axis. The value N(f)=1 corresponds to a maximum value of the frequency response N(f) for the case in which the unit E1, E2 is unloaded. A corresponding resonance frequency RF1 is also plotted, which is preferably at f=17 Hz. Furthermore, a frequency response in the form of a characteristic curve VK is shown for the case in which a unit E1, E2 is fully loaded with full incubation vessels. A corresponding resonance frequency RF2 or target frequency ZF is also plotted, which is preferably at f=16.67 Hz.

For the control of the magnetic drive units MA1, MA2 by the control unit SE, a target frequency ZF is provided, which is lower than the resonance frequency RF1. A corresponding characteristic curve is provided as the characteristic curve VK. The characteristic curve VK shows for example, a frequency response with a resonance frequency RF2 for the case that the incubator or the unit E1, E2 is fully loaded with incubation vessels containing corresponding reagents.

By selecting a target frequency ZF such that the target frequency ZF is below the resonance frequency RF1 of the units E1, E2 in the unloaded state, the case that further masses or mass elements in the form of the incubation vessels can be located in the units E1, E2 is advantageously represented during the control or regulation and thus the necessary energy to maintain a corresponding target frequency ZF is further minimized.

In the Figure 2 The control unit SE is shown, which determines control signals AS1, AS2 based on the sensor signals SIG1, SIG2 in order to control the magnetic drive units MA1, MA2. The Figure 9B shows a preferred embodiment of the control unit SE, which has sub-control units SE1, SE2 and SZ.

The sensor signal SIG1 is received at an interface IFA. The control unit SE also has an interface IFB for receiving the sensor signal SIG2. The sensor signal SIG1 is prepared and processed using a sub-unit SE1. The determined quantities or signals are then provided to the central sub-control unit SZ.

The same thing happens in the sub-control unit SE2 based on the signal SIG2. The central sub-control unit SZ then determines the control signals AS1, AS2 and makes them available at the corresponding interfaces IF1 and IF2.

The control signals AS1, AS2 are pulse width modulated signals, as signal PWMS in the Figure 8c The control signals AS1, AS2 are synchronized with respect to their duty cycle and are only modulated in their pulse width.

The Figure 9A shows details of a partial control unit SE1. The unit E1 is mechanically coupled to a base plate GP via the spring unit FE1 as described above. The position of the magnet M1 is monitored or detected by the sensor S1. The sensor S1 outputs the sensor signal SIG1 as a voltage signal. The partial control unit SE1 receives the sensor signal SIG1 at the interface IFA. The partial control unit SE1 derives an amplitude measurement signal ASIG1 from the sensor signal SIG1 and also preferably a frequency measurement signal FSIG1. Particularly preferably, the sub-control unit SE1, on the basis of the sensor signal SIG1, also generates a calibration signal KSIG1 for providing a signal indicating a zero position during a teaching procedure before the device is finally put into operation. The sensor signal SIG1 is amplified by a preamplifier VV1. This is then preferably followed by a high-pass filter HP followed by a low-pass filter TP1, so that a band-pass filter is formed. The resulting signal is then amplified by a further preamplifier VV2, so that the amplitude measurement signal ASIG1 is produced. The frequency measurement signal FSIG1 can then preferably be determined from the amplitude measurement signal by means of a comparator KO. The sensor signal SIG1 amplified by the preamplifier VV1 can also preferably be filtered by means of a low-pass filter TP2 in order to determine the calibration signal KSIG1. The determined signals ASIG1, FSIG1, KSIG1 can then be provided to the central sub-control unit SZ SZ. Preferably, at least the determined signals ASIG1, amplitude signal, and FSIG1, frequency signal, are provided to the central control unit SZ.

The partial control unit SE2 from the Figure 9B determines, on the basis of the second sensor signal SIG2, corresponding signals in the form of an amplitude measurement signal, a frequency measurement signal and preferably a calibration signal and also provides these to the central sub-control unit SZ. Further details are in the Figure 10 which illustrates an embodiment of the partial control unit SZ.

The aim of determining the control signals AS1, AS2 is that the resulting position or oscillation amplitudes of the two moving units behave as determined by the corresponding signals SIG1, SIG2 in the Figure 8D shown. The time is shown on the x-axis, with the time t2 preferably corresponding to a value of t1=(3/16.67) seconds, since the oscillation frequency to be controlled is preferably 16.67 Hz. The sensor voltage USIG in volts is plotted on the y-axis. The resulting respective oscillation frequencies of the respective units then have a phase offset of 180 degrees from one another. To do this, the control unit uses the sub-control unit SE1 to determine an amplitude measurement signal or an amplitude ASIG1 as well as an oscillation frequency or a frequency measurement signal FSIG1 on the basis of the sensor signal SIG1. Furthermore, the sub-control unit SE2 determines an amplitude measurement signal or an amplitude ASIG2 as well as an oscillation frequency or a frequency measurement signal FSIG2 and preferably a calibration signal KSIG2 on the basis of the sensor signal SIG2. The control unit then determines the control signals AS1, AS2, in particular by means of the sub-control unit SZ, in such a way that both units are controlled to a common oscillation amplitude and a common, identical target oscillation frequency.

In addition, the oscillation frequencies have a phase offset of 180 degrees from one another. The control carried out by the control unit SE is a control, in particular a PI control based on a common, identical target oscillation frequency.

The amplitude measurement signal ASIG1 is then rectified by a peak value rectifier SGR after an analog-digital conversion by an AD converter. The digital signal is then converted into millimeters by a conversion unit UE1. A difference formation unit DE1 receives a setpoint value of preferably 1 mm from a setpoint unit SW1 and then determines the control deviation RA1 as the difference, which is fed to a control unit RE1. The control unit RE1 carries out a PI control, which preferably uses a KP value of 0.03 as the value and a value of 0.6 as the KI value. A corresponding determination of a control deviation RA2 on the basis of the sensor signal ASIG2 is carried out by means of an AD converter AD, a peak value rectifier SGR and a conversion unit KE2, whereby here too the setpoint value is 1 mm, which is specified by the setpoint unit SW2, so that the difference unit RA2 determines the control deviation RA2. A PI control is then carried out in the control unit RE2 with the same KP and KI values of the unit RE1.

The frequency measurement signal FSIG1 is provided to an average value unit MWE via a digital input DI1. The same happens or is carried out by supplying the frequency measurement signal FSIG2 via a digital input DI2 and providing it to the average value unit MWE. A setpoint unit SWF provides a setpoint of preferably 16.67 Hz, so that a difference unit DEF then determines a difference between the frequency average FMW and the setpoint as a control deviation RAF. A control unit REF determines a PI control on the basis of the input signal or the control deviation RAF using a PI control and parameter values of KP=0.009 and KI=0.09 in such a way that respective internal control signals IS11 or IS22 are provided to the respective modulators PM1 or PM2.

A synchronous clock generator TG controls corresponding pulse width modulators PM1 and PM2. The pulse width modulator PM1 is controlled with regard to its pulse width by a signal IS1 of the amplitude control unit RE1 and a signal IS11 of the frequency control unit REF and then generates the control signal AS1. The pulse width modulator PM2 is controlled with regard to its pulse width by a signal IS2 of the amplitude control unit RE2 and a signal IS22 of the frequency control unit REF and then generates the control signal AS2.

As already mentioned, in a detailed view of the Figure 7A an orthogonal sectional view is shown, in which a cross section through the receptacles A is visible as well as an incubation vessel IG introduced into a receptacle A. A corresponding perspective view of such a sectional view is shown in the Figure 7B can be seen, whereby the incubation vessel IG was also introduced in a shot A.

The incubation vessel IG preferably tapers in a lower region UB and has a circumferential edge R in its upper region, which projects beyond the side walls SWE of the vessel.

When introduced into a receptacle A, the incubation vessel IG comes to rest with its edge R on an upper side OSE of the unit E1. As a result, the incubation vessel IG is at least partially held in the receptacle A. Furthermore, the incubation vessel IG is preferably held by at least partially creating a positive connection between the receptacle A and the incubation vessel IG.

The Figure 6A shows an incubation vessel IG with its edge R and the side walls SWE, whereby the incubation vessel IG is held by a gripping unit G. Such a representation is also shown in an oblique view in the Figure 6B shown.

A first part T1 of a clamping mechanism of the gripping unit G grips the incubation vessel IG on two sides below the edge R or on the underside UR of the edge. Furthermore, a second sub-unit T2 of a clamping mechanism of the gripping unit G grips the incubation vessel by pressing this second sub-unit T2 from above onto the top OR of the edge of the incubation vessel IG by a spring unit GF. The sub-units T1 and T2 of the gripping unit thus interact to generate a frictional force for holding the incubation vessel. This allows the gripping unit G to grip the incubation vessel IG.

In the Figure 4 a schematic diagram of a preferred embodiment of a laboratory machine LA according to the invention is shown. The laboratory machine LA has a gripping unit G for gripping incubation vessels IG. The laboratory machine LA also has a magazine MAG with several incubation vessels IG. By means of the gripping unit G, incubation vessels IG can be transported from the magazine MAG to a pipetting unit PE. In a preferably provided pipetting base PB of the pipetting unit PE, a receptacle A for receiving an incubation vessel is then provided. IG is provided. The pipetting unit PE can therefore accommodate an incubation vessel IG in particular in a receptacle A.

The laboratory machine LA also has a container B1 with a patient sample liquid PPF. The laboratory machine LA also has a container B2 with a buffer liquid PUF. The laboratory machine LA also has a container B3 with a bead liquid BF. The laboratory machine also has a container B4 with a label liquid AF, which has antibodies marked with a chemiluminescence label or antigens marked with a chemiluminescence label.

The laboratory machine LA further comprises a device V according to the invention.

The gripping unit G is therefore further designed to bring incubation vessels IG from the pipetting unit PE into respective receptacles of the respective units E1, E2 of the device V and to remove them again, in particular to transport incubation vessels from the device V back to the pipetting unit PE. For this purpose, the gripping unit G is preferably displaceable or movable in the X direction, Y direction and Z direction. The gripping unit G can automatically grip incubation vessels IG and also release or put them down again.

The pipetting unit PE has one or more pipetting needles PN, which are preferably movable or displaceable in the X direction, Y direction and Z direction. Using such pipetting needles PN, various of the liquids PPF, PUF, WF, AF can be pipetted from the containers B1, B2, B3, B4 into an incubation vessel IG or aspirated from it.

To carry out a chemiluminescence assay, the laboratory machine LA preferably further comprises a reading station LS. Thus, the laboratory machine LA preferably further comprises a container B5 with a liquid or trigger liquid E, which in turn comprises an enzyme for conversion in the chemiluminescence reaction.

Preferably, the enzyme E is introduced into an incubation vessel IG by a dispensing unit DIS, which is preferably located in a receptacle A of a base BA. The optical radiation or optical signal OS that is generated can preferably be detected by means of a reading unit LE. Preferably, after the optical signal OS has been detected, a corresponding digital signal DSI can then be evaluated by a computing unit RC and preferably transmitted via a data interface of the Computing unit RC is sent via a data network. The computing unit RC is preferably an integral part of the laboratory machine LA. The reading station LS therefore has the reading unit LE and the computing unit RC.

The laboratory automation device is in particular a laboratory automation device for processing a patient sample using a chemiluminescence assay to detect a target antigen or a target antibody in the patient sample.

The patient sample is in particular a liquid patient sample. The patient sample liquid can have a homogeneous liquid phase. The patient sample liquid is preferably a human sample taken for diagnostic examination and optionally prepared, preferably e.g. blood, preferably blood serum, urine, cerebrospinal fluid, saliva or sweat.

For many automated systems, so-called chemilumiscence methods or chemilumiscence assays are used to detect a specific antigen or target antigen or a specific antibody or target antibody in a patient sample in order to gain knowledge about a patient's possible state of health. Beads in particular are used as carriers for reagents. For example, the beads can be carriers for immobilized antigens to which antibodies or target antibodies to be detected in human samples bind. The beads are usually supplied in aqueous solutions and stored until use, the so-called bead liquid. The beads are in particular magnetizable particles, in particular metallic, magnetizable particles. If such beads are incubated with a liquid patient sample, the presence of the target antibodies leads to the formation of an antigen-antibody complex that is immobilized on the bead. After a washing step with a rinsing liquid or buffer liquid, this complex can be incubated with suitable reagents, in particular called a conjugate. These are in particular label liquids containing secondary antibodies labelled with a chemiluminescence label, particularly preferably in the form of acridinium. This secondary antibody is preferably an anti-human antibody, preferably anti-human IgG antibody. The commercially available so-called chemiluminescence laboratory machines are based on this principle, which can preferably also be a random access analyzer. To generate an optical signal, a solution or trigger solution with an enzyme is then added at the end of the chemiluminescence process in order to bring about a chemiluminescence reaction between the enzyme and the chemiluminescence label, so that an optical signal is generated. The The resulting optical signal corresponds to the antibody concentration in the patient sample and can be automatically converted into a concentration by the laboratory machine after detection. The label liquid is also called conjugate liquid.

To detect an antigen instead of an antibody, antibody-coated magnetic particles, so-called beads, are incubated with the patient sample and an antigen-specific biotinylated antibody. During the incubation, the antigen is bound by both the magnetic particle-coupled antibody and the biotinylated antibody. In a further step, conjugate is added that binds the biotinylated antibody. The reaction mixture is then mixed with the trigger solution, which induces a chemiluminescence reaction.

Immunodiagnostic tests or assays that work according to this principle are described in the state of the art for numerous indications, for example in EP 2 199 303 , DE 10 2009033281 , WO 2010/009457 or EP12183919.5 Principles of a chemiluminescence process are also described in the EP 3 160 646 B1 described.

Suitable reagents are described in the prior art, for example in Ireland, D., and Samuel, D. (1989), "Enhanced Chemiluminescence ELISA for the detection for antibody to hepatitis B virus surface antigen", J. Biolum. Chemilumin., 159-163 and in " Acridinium Esters as Highly Specific Activity Labels in Immunoassays," Clin. Chemistry 19:1474-1478 (1984 ) and in US4842997 A .

Inhomogeneous bead liquids pose a particular problem, for example suspensions of beads in an aqueous solution whose density is higher than that of water, so that the beads can sink to the bottom. During incubation, the beads can sediment in an incubation vessel. Alternatively, such beads can easily accumulate on surfaces in the liquid phase. The incubation vessels are therefore regularly moved or vibrated during incubation.

The bead liquid can also have an inhomogeneous phase and either comprise two immiscible or only partially miscible liquids or a solid substance in a liquid. In a preferred embodiment, the liquid is beads in aqueous solution. Such beads can be provided with biological reagents immobilized on them, e.g. polypeptides that function as antigens. Various beads are available for numerous applications, predominantly based on carbohydrates (e.g. agarose) or plastics. They contain active or activatable chemical groups such as carboxyl groups, which can be used for the immobilization of reagents, e.g. antibodies or antigens. Preferably, the beads have an average diameter of 0.2 mm to 5 mm, 0.5 mm to 1 mm, 0.75 mm to 100 mm or 1 mm to 10 mm. The beads can be coated with an antigen that binds to a diagnostically relevant antibody, or with affinity ligands, for example biotin or glutathione. Preferably, the liquid comprises the beads in the form of an aqueous suspension with a bead content of 10 to 90%, more preferably 20 to 80, more preferably 30 to 70, even more preferably 40 to 60% (w/w).

In a particularly preferred embodiment, these are paramagnetic beads that can easily be concentrated on a surface using a magnet. For this purpose, commercially available paramagnetic beads usually contain a paramagnetic mineral, for example iron oxide.

The buffer liquid can also be referred to as rinsing liquid. Such buffer liquids or rinsing liquids are known to the person skilled in the art, in particular from EP 3 160 646 B1 .

The features disclosed in the above description, the claims and the drawings can be important both individually and in any combination for the realization of embodiments in their various configurations and - unless the description indicates otherwise - can be combined with one another in any way. Although some aspects have been described in connection with a device, in particular in the form of a laboratory machine, it is understood that these aspects also represent a description of the corresponding method, so that a block or a component of a device can also be understood as a corresponding method step or as a feature of a method step. Analogously, aspects that have been described in connection with or as a method step also represent a description of a corresponding block or detail or feature of a corresponding device or laboratory machine.

Depending on specific implementation requirements, embodiments of the invention can be implemented in hardware or in software, in particular a control unit and/or a reading unit and/or a reading station. A programmable hardware component can in particular be a microcontroller, a processor, a computer processor (CPU = Central Processing Unit), a graphics processor (GPU = Graphics Processing Unit), a computer, a computer system, an application-specific integrated circuit (ASIC = Application-Specific Integrated Circuit), an integrated circuit (IC = Integrated Circuit), a system on chip (SOC = System), a programmable logic element or a field-programmable gate array with a microprocessor (FPGA = Field Programmable Gate Array) or only an FPGA without a microcontroller.

Claims (13)

Device for incubating multiple patient samples using multiple incubation vessels, having - a first unit (E1) with respective receptacles (A) for respective incubation vessels (IG), - and a second unit (E2) with respective holders (A) for respective incubation vessels (IG), wherein both of the respective units (E1, E2) are movably mounted along a common linear guide axis (LFA) in their respective location positions, further comprising - respective sensors (S1, S2) for providing respective sensor signals (SIG1, SIG2), each of which indicates one of the respective location positions, - furthermore respective magnetic drive units (MA1, MA2) for respective changes of the respective location positions, - and also a control unit (SE) which is designed to control the respective magnetic drive units (MA1, MA2) on the basis of the respective sensor signals (SIG1, SIG2) in order to bring about the respective changes in the respective location positions. Device according to claim 1,
wherein the two units (E1, E2) are each mounted and guided along the common linear guide axis (LFA) in such a way that they have only one common translational degree of freedom. Device according to claim 1,
wherein a respective unit (E1, E2) is mechanically coupled to a common base plate (GP) via a respective spring unit (FE1, FE2). Device according to claim 3,
wherein a respective unit (E1, E2) is mechanically coupled to the common base plate (GP) via a respective spring unit (FE1, FE2) such that the respective Unit (E1, E2) together with the respective spring unit (FE1, FE2) forms a respective spring-mass oscillation system. Device according to claim 1,
wherein the control unit (SE) is designed to control the magnetic drive units (MA1, MA2) such that the units (E1, E2) are each kept in vibration with a substantially equal vibration amplitude in the direction of the linear guide axis (LFA). Device according to claim 1,
wherein the control unit (SE) is designed to control the magnetic drive units (MA1, MA2) by means of a control based on the sensor signals (SIG1, SIG2) such that the resulting respective oscillation frequencies of the respective units are substantially equal and that the respective oscillation frequencies have a phase offset of substantially 180 degrees from one another. Device according to claim 1, wherein the control unit (SE) is designed to determine a respective current amplitude and a respective oscillation frequency for a respective unit (E1, E2) on the basis of a respective sensor signal (SIG1, SIG2), and wherein the control unit (SE) is designed to regulate both units (E1, E2) to a common oscillation amplitude and a common, identical target oscillation frequency. Device according to claim 3 or 4, wherein both units (E1, E2) with the respective spring units (FE1, FE2) each have a spring-mass oscillation system with the same resonance frequency (RF1) in the unloaded state and the target oscillation frequency is below this resonance frequency (RF1). Device according to claim 1,
wherein the control unit (SE) is designed to carry out a PI control with respect to a common, identical target oscillation frequency. Device according to claim 1,
wherein both units (E1, E2) have a respective heating unit (H1, H2). Laboratory machine (LA) with a device (V) according to claim 1,
further comprising - a magazine (MAG) with a plurality of incubation vessels (IG), - a container (B1) with a patient sample fluid (PPF), a container (B2) with a buffer fluid (PUF), a container (B3) with a bead fluid (BF) containing antigens or beads coated with antibodies and a container (B4) with a label fluid (AF) containing antibodies or antigens labelled with a chemiluminescence label, - a pipetting unit (PE) which is designed to dispense at least a portion of the patient sample liquid, at least a portion of the buffer liquid, at least a portion of the bead liquid and at least a portion of the label liquid into the incubation vessels and to aspirate them from the incubation vessels, - and further a gripping unit (G) which is designed to grip incubation vessels • from the magazine (MAG) to the pipetting unit (PE) • as well as to transport them from the pipetting unit (PE) into the respective receptacles (A), to remove them from the respective receptacles (A) and to transport them back to the pipetting unit (PE). Laboratory machine according to claim 11, further comprising a container (B5) with a liquid comprising an enzyme (E) for implementing a chemiluminescence reaction, in particular further comprising a dispensing unit for introducing the liquid comprising the enzyme into an incubation vessel, and further comprising a reading unit (LE) for detecting an optical signal (OS) of a chemiluminescence reaction. Laboratory machine according to claim 11,
wherein the magnetic drives (MA1, MA2) are arranged such that beads contained in the bead liquid (BF) are not significantly magnetically influenced by magnetic fields of the magnetic drives (MA1, MA2).

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